The parasympathetic limb, i.e., the vagus nerve, is a major component of the autonomic nervous system which regulates the function of various organs and tissues throughout the body. Sensory stimuli elicit neural signals (i.e.,action potentials) traveling in the vagus nerve via afferent fibers to the central nervous system which in turn sends neural signals to effector organs via efferent vagal fibers; known as vagal reflexes. In addition, sensory stimuli can elicit localized release of biologically active compounds (i.e., neuropeptides) from afferent nerve terminals, independent of afferent traffic traveling to the central nervous system; known as axonal reflexes. The vagus nerve maintains a basal level of activity, evidenced by the output of the efferent vagal fibers, or tone. Vagal tone is increased or decreased depending upon the body's needs, generally in response to internal or external sensory stimuli. The former can be either central or peripheral. The effects of the vagus nerve are mediated by the neurotransmitter acetylcholine, released from efferent nerve terminals, activating muscarinic cholinergic receptors on target cells.
Alteration of vagal tone is used in humans in the acute management of pathophysiologic conditions and therapy of certain diseases. For example, certain cardiac pathologies are associated with vagally mediated slowing of the heart rate (i.e., bradyarrhythmias). This slowing can hemodynamically compromise a patient's welfare. Also, there is considerable evidence that vagal reflexes and vagal afferent axonal reflexes contribute to the pathophysiology and symptomatology of asthma and other obstructive pulmonary diseases.
Existing approaches for alteration of vagal tone are based on pharmacologic modulation of the function of the vagal efferent fibers. For instance, vagal tone can be modulated by blockade of muscarinic cholinergic receptors as well as by the inhibition of acetylcholinesterase, an enzyme which degrades acetylcholine. Indeed, anticholinergic drugs are very effective in the treatment of bradyarrhythmias associated with acute myocardial ischemia. These drugs are also effective bronchodilators in chronic obstructive pulmonary diseases. However, there is presently no therapeutic approach which targets the axonal reflexes which exacerbate certain pathophysiologic conditions such as asthmatic bronchoconstriction.
The number of people in the United States and other developed countries suffering from asthma has doubled over the last twenty years. The cost of illness related to asthma in the United States was estimated to be 6.2 billion dollars in 1990. Today, it is estimated that 10% of the world's population suffers from asthma. Furthermore, the number of asthma deaths worldwide continues to increase. This trend in increasing mortality due to asthma is paradoxical in view of the decreased mortality from other diseases and our better understanding of the pathophysiology of asthma. This situation is probably due, at least in part, to the lack of new therapeutic modalities including those which also target the neural component of the disease.
The vagus nerve also mediates neurogenic human fainting (i.e., vasovagal syncope). A vasovagal reaction is characterized by an inappropriate decrease in blood pressure and/or heart rate. Patients suspected of suffering from vasovagal syncope are subjected to a clinical test (i.e., tilt test) in which the induction of fainting is attempted by head-up tilt in the presence or absence of drugs (e.g., isoproterenol). This is a tedious and expensive test. Furthermore, there is presently no diagnostic procedure available to determine the severity of this pathology quantitatively.
Adenosine 5'-triphosphate (ATP) is a purine nucleotide found in every cell of the human body where it plays a major role in cellular metabolism and energetics. Once outside of cells, however, ATP exerts different effects on various tissues and organs. The actions of extracellular ATP are known to be mediated by specific cell surface receptors, P.sub.2 -purinoceptors. These receptors are subdivided into two families: P.sub.2x and P.sub.2y (Abbracchio and Burnstock, Pharmacol Ther. (1994) 64, 445-475). Classification is based upon certain aspects of the signal transduction initiated by the activation of these receptors as well as the relative agonist potencies of ATP and ATP analogues in different systems. For example P.sub.2x -purinoceptor-mediated responses are characterized by the order of agonist potencies of .alpha., .beta.-methylene ATP which is greater than .beta., .gamma.-methylene ATP which is greater than ATP and 2methyl-thio ATP (those two being equal). Thus, it has been recognized that purinoceptors are unique and their stimulation activates specific mechanisms. Extracellular ATP is known to affect neural elements via the activation of a P.sub.2x -purinoceptor.
Trezise et al., Br. J. Pharmacol.(1993) 110, 1055-1060, have shown that ATP can depolarize rat vagal fibers in vitro and that this action is mediated by P.sub.2x - purinoceptors.
However, such findings are not applicable to the autonomic nervous system of humans for a number of reasons. First, tests with single cells do not address the problems of purine metabolism associated with whole tissue. Further, it is uncertain whether tissues in vitro express the same receptor types as in vivo. In addition, work performed with ATP in rats can not be extrapolated to humans because rats lack certain specific type of afferent/efferent reflex loops triggered by ATP which are found only in cats, dogs and humans.
ATP has been employed as a therapeutic in human patients. For example, ATP has been used for many years in the acute management of paroxysmal supraventricular tachycardia. However, it is believed that the mechanism of ATP's action in this setting involves the degradation of ATP to adenosine and the action of adenosine on the specialized tissue of the heart (i.e., atrio-ventricular node). Indeed, the use of adenosine in this setting is the subject of Belardinelli et al., U.S. Pat. No. 4,673,563. ATP has also been shown to be effective against cancer in animal models and in humans. However, the mechanism of action of ATP in this setting involves the immune system and/or direct action on tumor cells and is independent of the autonomic nervous system. The use of ATP as anti-cancer therapy is the subject of Rapaport, U.S. Pat. No. 5,049,372.
The present invention provides a unique approach to modulating vagal tone and vagal axonal reflexes in humans through the activation and blockade of P.sub.2 -purinoceptors on afferent vagal nerve terminals in vivo.